The current melanoma "epidemic" is primarily affecting older men and women in our Veteran population due to age, sun and chemical exposure. During melanoma tumor progression amplification of aurora kinases A and B and/or the deregulation of NF-?B lead to aneuploidy, enhanced cell proliferation, escape from apoptosis, enhanced production of inflammatory mediators and tumor progression. We have preliminary data showing that xenografts of some human melanoma tumors are growth inhibited when aurora A kinase is blocked, while xenografts from other melanoma lesions respond to an IKK? inhibitor. We hypothesize that constitutive activation of IKK? and/or aurora kinase (AIK) amplification can contribute to melanoma tumor progression and that inhibition of these pathways will inhibit tumor growth. Moreover, we hypothesize that human melanoma gene expression profiles can predict which tumors will respond to AIK inhibitors and which will respond to IKK? inhibitors. There are three specific aims for this project: 1) to characterize the expression of aurora kinase A, B, C during melanoma tumor progression using immunohistochemical analysis of tissue microarrays and to determine how the over-expression of IKK/ AIK kinases affect melanocytes and tumor growth;2) to determine whether inhibiting both IKK and AIK pathways may prove to be more efficacious for treatment of melanoma tumors than by targeting each individual kinase alone and to determine how inhibition of IKK and AIK affect the anti-tumor host defense;3) to characterize the gene expression profiles for human melanoma tumors that respond or do not respond to AIK or IKK? inhibitors. Using immunohistochemical analyses of tissue microarrays we will examine the expression pattern of aurora kinases and phosphorylated (RelA/p65) of nevi, dysplastic nevi, primary and metastatic melanoma lesions during tumor progression. We will utilize an inducible expression system to alter the expression of AurA and IKK? in melanocytes and melanoma cells in vitro to determine the consequences of over-activation of these two pathways. We will examine the response of melanoma tumors to inhibitors of IKK?, AIKs, and combinations thereof in a murine xenograft model. Finally, using gene expression microarray analysis, we will determine the expression profiles that distinguish between drug responders versus non-responders. The data derived from this proposal will provide key insights for better design of clinical trials for melanoma patients which should positively impact our Veteran population.
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